Chantal Depondt

Publications of Chantal Depondt

• Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions.

  Authors: Mark McCormack, Thomas J Urban, Kevin V Shianna, Nicole Walley, Massimo Pandolfo, Chantal Depondt, Elijah Chaila, Gerard D O'Conner, Dalia Kasperavičiūtė, Rodney A Radtke, Erin L Heinzen, Sanjay M Sisodiya, Norman Delanty, Gianpiero L Cavalleri

  Pharmacogenomics. 03/2012; 13(4):399-405.

  An association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other commonAn association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other common variants across the genome as markers for cutaneous adverse drug reactions (cADRs) attributed to lamotrigine and phenytoin. We recruited patients with lamotrigine-induced cADRs (n = 46) and patients with phenytoin-cADRs (n = 44) and the 1958 British birth cohort was used as a control (n = 1296). HLA-A*3101 was imputed from genome-wide association study data. We applied genome-wide association to study lamotrigine- and phenytoin-induced cADR, and total cADR cases combined. Neither HLA-A*3101 nor any other genetic marker significantly predicted lamotrigine- or phenytoin-induced cADRs. HLA-A*3101 does not appear to be a predictor for lamotrigine- and phenytoin-induced cADRs in Europeans. Our genome-wide association study results do not support the existence of a clinically relevant common variant for the development of lamotrigine- or phenytoin-induced cADRs. As a predictive marker, HLA-A*3101 appears to be specific for carbamazepine-induced cADRs.

• Genetic and environmental correlates of topiramate-induced cognitive impairment.

  Authors: Elizabeth T Cirulli, Thomas J Urban, Susan E Marino, Kristen N Linney, Angela K Birnbaum, Chantal Depondt, Deborah K Attix, Rodney A Radtke, David B Goldstein

  Epilepsia. 11/2011; 53(1):e5-8.

  Topiramate is an antiepileptic drug that has marked treatment-limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe sideTopiramate is an antiepileptic drug that has marked treatment-limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe side effects occur only in certain individuals, identifying genetic or environmental variables that influence cognitive response would be of great utility in determining whether to administer this drug to a patient. We gave an acute 100 mg oral dose of topiramate to 158 healthy volunteers and measured how the drug changed their performance on a diverse battery of cognitive tests. We found a wide range of responses to topiramate, and we demonstrated that not all tests in the battery were equally affected. There was no correlation between the effect of topiramate and either education level or baseline cognitive performance. Of interest, there was an up to 55-fold variation in the topiramate plasma levels of the participants. Our genome-wide association study (GWAS) of cognitive response did not reveal any genome-wide significant associations; the study was powered to find variants explaining at least 25% of the variation in cognitive response. Combining the results of this GWAS with a retrospective study of cognitive complaints in 290 epilepsy patients who received topiramate as part of their treatment also did not result in a significant association. Our results support the need for additional genetic studies of topiramate that use larger sample sizes.

• Spinocerebellar Ataxia Types 1, 2, 3 and 6: the Clinical Spectrum of Ataxia and Morphometric Brainstem and Cerebellar Findings.

  Authors: Heike Jacobi, Till-Karsten Hauser, Paola Giunti, Christoph Globas, Peter Bauer, Tanja Schmitz-Hübsch, László Baliko, Alessandro Filla, Caterina Mariotti, Maria Rakowicz [......] Jun-Suk Kang, Susanne Ratzka, Berry Kremer, Dennis A Stephenson, Béla Melegh, Massimo Pandolfo, Sophie Tezenas du Montcel, Johannes Borkert, Jörg B Schulz, Thomas Klockgether

  Cerebellum (London, England). 06/2011;

  To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, aTo assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1-3), speech (item 4) and the limb kinetic subscore (items 5-8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose-finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

• Genomic microdeletions associated with epilepsy: not a contraindication to resective surgery.

  Authors: Claudia B Catarino, Dalia Kasperavičiūtė, Maria Thom, Gianpiero L Cavalleri, Lillian Martinian, Erin L Heinzen, Thomas Dorn, Thomas Grunwald, Elijah Chaila, Chantal Depondt, Günter Krämer, Norman Delanty, David B Goldstein, Sanjay M Sisodiya

  Epilepsia. 06/2011; 52(8):1388-92.

  Several recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of suchSeveral recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of such genetic abnormalities in patients being evaluated for surgical treatment might raise concern that a genetic defect, possibly widely expressed in the brain, will affect surgical outcome. A reevaluation was undertaken of clinical presurgical data, histopathology of surgical specimen, and postsurgical outcome in patients with mesial temporal lobe epilepsy (MTLE) who have had surgical treatment for their drug-resistant seizures, and who have been found to have particular genomic microdeletions. Three thousand eight hundred twelve patients with epilepsy were genotyped and had a genome-wide screen to identify copy number variation. Ten patients with MTLE, who had resective epilepsy surgery, were found to have 16p13.11 microdeletions or other microdeletions >1 Mb. On histopathology, eight had classical hippocampal sclerosis (HS), one had nonspecific findings, and one had a hamartoma. Median postsurgical follow-up time was 48 months (range 10-156 months). All patients with HS were seizure-free after surgery, International League Against Epilepsy (ILAE) outcome class 1, at last follow-up; the patient with nonspecific pathology had recurrence of infrequent seizures after 7 years of seizure freedom. The patient with a hamartoma never became seizure-free.   Large microdeletions can be found in patients with "typical" MTLE. In this small series, patients with MTLE who meet criteria for resective surgery and harbor large microdeletions, at least those we have detected, can have a good postsurgical outcome. Our findings add to the spectrum of causal heterogeneity of MTLE + HS.

• HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.

  Authors: Mark McCormack, Ana Alfirevic, Stephane Bourgeois, John J Farrell, Dalia Kasperavičiūtė, Mary Carrington, Graeme J Sills, Tony Marson, Xiaoming Jia, Paul I W de Bakker [......] Massimo Pandolfo, Werner Pichler, B Kevin Park, Chantal Depondt, Sanjay M Sisodiya, David B Goldstein, Panos Deloukas, Norman Delanty, Gianpiero L Cavalleri, Munir Pirmohamed

  The New England journal of medicine. 03/2011; 364(12):1134-43.

  Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlatedCarbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).

• Depression comorbidity in spinocerebellar ataxia.

  Authors: Tanja Schmitz-Hübsch, Mathieu Coudert, Sophie Tezenas du Montcel, Paola Giunti, Robyn Labrum, Alexandra Dürr, Pascale Ribai, Perrine Charles, Christoph Linnemann, Ludger Schöls [......] Chantal Depondt, Jun-Suk Kang, Jörg B Schulz, Thomas Klopstock, Nicole Lossnitzer, Bernd Löwe, Caroline Frick, Daniela Rottländer, Thomas E Schlaepfer, Thomas Klockgether

  Movement disorders : official journal of the Movement Disorder Society. 03/2011; 26(5):870-6.

  This is a description of the prevalence and profile of depressive symptoms in dominant spinocerebellar ataxia (SCA). Depressive symptoms were assessed in a convenience sample of 526 geneticallyThis is a description of the prevalence and profile of depressive symptoms in dominant spinocerebellar ataxia (SCA). Depressive symptoms were assessed in a convenience sample of 526 genetically confirmed and clinically affected patients (117 SCA1, 163 SCA2, 139 SCA3, and 107 SCA6) using the Patient Health Questionnaire (PHQ). In addition, depressive status according to the examiner and the use of antidepressants was recorded. Depression self-assessment was compared with an interview-based psychiatric assessment in a subset of 26 patients. Depression prevalence estimates were 17.1% according to the PHQ algorithm and 15.4% when assessed clinically. The sensitivity of clinical impression compared with PHQ classification was low (0.35), whereas diagnostic accuracy of PHQ compared with psychiatric interview in the subset was high. Antidepressants were used by 17.7% of patients and in >10% of patients without current clinically relevant depressive symptoms. Depression profile in SCA did not differ from a sample of patients with major depressive disorder except for the movement-related item. Neither depression prevalence nor use of antidepressants differed between genetic subtypes, with only sleep disturbance more common in SCA3. In a multivariate analysis, ataxia severity and female sex independently predicted depressive status in SCA. The PHQ algorithmic classification is appropriate for use in SCA but should stimulate further psychiatric evaluation if depression is indicated. Despite a higher risk for depression with more severe disease, the relation of depressive symptoms to SCA neurodegeneration remains to be shown.

• Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study.

  Authors: Dalia Kasperaviciūte, Claudia B Catarino, Erin L Heinzen, Chantal Depondt, Gianpiero L Cavalleri, Luis O Caboclo, Sarah K Tate, Jenny Jamnadas-Khoda, Krishna Chinthapalli, Lisa M S Clayton [......] Kai J Eriksson, Reetta K Kälviäinen, Colin P Doherty, Nicholas W Wood, Massimo Pandolfo, John S Duncan, Josemir W Sander, Norman Delanty, David B Goldstein, Sanjay M Sisodiya

  Brain : a journal of neurology. 07/2010; 133(Pt 7):2136-47.

  Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies havePartial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio<1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

• Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

  Authors: Erin L Heinzen, Rodney A Radtke, Thomas J Urban, Gianpiero L Cavalleri, Chantal Depondt, Anna C Need, Nicole M Walley, Paola Nicoletti, Dongliang Ge, Claudia B Catarino [......] Julie Huxley-Jones, Mohamad Mikati, William B Gallentine, Aatif M Husain, Patrick G Buckley, Ray L Stallings, Mihai V Podgoreanu, Norman Delanty, Sanjay M Sisodiya, David B Goldstein

  American journal of human genetics. 05/2010; 86(5):707-18.

  Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structuralDeletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

• Self-rated health status in spinocerebellar ataxia--results from a European multicenter study.

  Authors: Tanja Schmitz-Hübsch, Mathieu Coudert, Paola Giunti, Christoph Globas, Laszlo Baliko, Roberto Fancellu, Caterina Mariotti, Alessandro Filla, Maryla Rakowicz, Perrine Charles [......] Ludger Schöls, Elszbieta Zdzienicka, Jun-Suk Kang, Susanne Ratzka, Berry Kremer, Jörg B Schulz, Thomas Klopstock, Bela Melegh, Sophie Tezenas du Montcel, Thomas Klockgether

  Movement disorders : official journal of the Movement Disorder Society. 02/2010; 25(5):587-95.

  Patient-based measures of subjective health status are increasingly used as outcome measures in interventional trials. We aimed to determine the variability and predictors of subjective healthPatient-based measures of subjective health status are increasingly used as outcome measures in interventional trials. We aimed to determine the variability and predictors of subjective health ratings in a possible target group for future interventions: the spinocerebellar ataxias (SCAs). A consecutive sample of 526 patients with otherwise unexplained progressive ataxia and genetic diagnoses of SCA1 (117), SCA2 (163), SCA3 (139), and SCA6 (107) were enrolled at 18 European referral centers. Subjective health status was assessed with a generic measure of health related quality of life, the EQ-5D (Euroqol) questionnaire. In addition, we performed a neurological examination and a screening questionnaire for affective disorders (patient health questionnaire). Patient-reported health status was compromised in patients of all genotypes (EQ-5D visual analogue scale (EQ-VAS) mean 61.45 +/- 20.8). Specifically, problems were reported in the dimensions of mobility (86.9% of patients), usual activities (68%), pain/discomfort (49.4%), depression/anxiety (46.4%), and self care (38.2%). Multivariate analysis revealed three independent predictors of subjective health status: ataxia severity, extent of noncerebellar involvement, and the presence of depressive syndrome. This model explained 30.5% of EQ-VAS variance in the whole sample and might be extrapolated to other SCA genotypes.

• Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6.

  Authors: Christoph Globas, Sophie Tezenas du Montcel, Laslo Baliko, Syliva Boesch, Chantal Depondt, Stefano Didonato, Alexandra Durr, Alessandro Filla, Thomas Klockgether, Caterina Mariotti, Bela Melegh, Maryla Rakowicz, Pascale Ribai, Rafal Rola, Tanja Schmitz-Hubsch, Sandra Szymanski, Dagmar Timmann, Bart P Van de Warrenburg, Peter Bauer, Ludger Schols

  Movement disorders : official journal of the Movement Disorder Society. 09/2008;

  Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA)Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We investigated early symptoms in 287 patients with SCA1, SCA2, SCA3, or SCA6 and calculated the influence of CAG repeat length on age of onset depending on (1) the definition of disease onset, (2) people defining onset, and (3) duration of symptoms. Gait difficulty was the initial symptom in two-thirds of patients. Double vision, dysarthria, impaired hand writing, and episodic vertigo preceded ataxia in 4% of patients, respectively. Frequency of other early symptoms did not differ from controls and was regarded unspecific. Data about disease onset varied between patients and relatives for 1 year or more in 44% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance and cases with symptoms for more than 10 years were excluded. Under these conditions, CAG repeat length determined 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3, and 41% in SCA6 demonstrating substantial influence of nonrepeat factors on disease onset in all SCA subtypes. Identification of these factors is of interest as potential targets for disease modifying compounds. In this respect, recognition of early symptoms that develop before onset of ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA. (c) 2008 Movement Disorder Society.

• Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

  Authors: Gianpiero L Cavalleri, Michael E Weale, Kevin V Shianna, Rinki Singh, John M Lynch, Bronwyn Grinton, Cassandra Szoeke, Kevin Murphy, Peter Kinirons, Deirdre O'Rourke [......] Terence J O'Brien, Josemir W Sander, John S Duncan, Ingrid E Scheffer, Samuel F Berkovic, Nicholas W Wood, Colin P Doherty, Norman Delanty, Sanjay M Sisodiya, David B Goldstein

  Lancet neurology. 12/2007; 6(11):970-80.

  BACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development andBACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. METHODS: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. FINDINGS: We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. INTERPRETATION: The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

• A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy.

  Authors: Gianpiero L Cavalleri, Nicole M Walley, Nicole Soranzo, John Mulley, Colin P Doherty, Ashish Kapoor, Chantal Depondt, John M Lynch, Ingrid E Scheffer, Armin Heils [......] Peter Kinirons, Sonia Gandhi, Parthasarathy Satishchandra, Nicholas W Wood, Anuranjan Anand, Thomas Sander, Samuel F Berkovic, Norman Delanty, David B Goldstein, Sanjay M Sisodiya

  Epilepsia. 05/2007; 48(4):706-12.

  PURPOSE: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recentlyPURPOSE: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls. METHODS: The strongest candidate causal variant from the original report (rs3918149) was genotyped across all five cohorts. In an effort to identify novel candidate causal polymorphisms, previously unscreened regions of UTR were resequenced. RESULTS: We observed a significant effect in a small sample recruited in Britain (genotype p = 0.001, allele p = 0.001), a borderline significant effect in a sample recruited in Ireland and no association in larger samples of German, Australian, and Indian populations. There was no association with other common forms of epilepsy or any other clear candidate casual variants in or near the BRD2 region. CONCLUSIONS: The replication of an effect in the British cohort and suggestive evidence from that recruited in Ireland but lack of replication from the larger German, Australian, and Indian cohorts is surprising and difficult to explain. Further replication in carefully matched populations is required. Results presented here do not, however, support a strong effect for susceptibility to JME across populations of European descent.

• A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose.

  Authors: Sarah Tate, Rinki Singh, Chin-Chuan Hung, John Tai, Chantal Depondt, Gianpiero Cavalleri, Sanjay Sisodiya, David Goldstein, Horng-Huei Liou

  Pharmacogenetics and genomics. 10/2006; 16(10):721-726.

  OBJECTIVES: A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A geneOBJECTIVES: A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target. METHODS: We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin. We also related genotype to phenytoin serum levels at maximum dose and at maintenance dose of phenytoin. We genotyped the polymorphism using an Applied Biosystems Taqman assay. RESULTS: The polymorphism is associated with phenytoin serum concentration at maintenance dose (P=0.03). In a reduced cohort of 71 patients receiving phenytoin monotherapy this association is also significant (P=0.03). Neither association remains significant after Bonferroni correction for multiple testing. CONCLUSIONS: These results are not a replication of the original study. They do, however, support the hypothesis that this polymorphism influences the clinical use of phenytoin. They also demonstrate the utility of using multiple phenotypes in pharmacogenetics studies, particularly when attempting to separate pharmacokinetic and pharmacodynamic effects. As the SCN1A polymorphism affects phenytoin pharmacodynamics, it is particularly useful to obtain data on serum levels in addition to dose because association of a pharmacodynamic variant may be stronger with serum levels than dose as the serum level may eliminate or reduce pharmacokinetic variability.

• Genetic association studies in epilepsy pharmacogenomics: lessons learnt and potential applications.

  Authors: Chantal Depondt, Simon D Shorvon

  Pharmacogenomics. 08/2006; 7(5):731-45.

  Although epilepsy is one of the most common neurological disorders and genetic factors are well known to play a role in response to antiepileptic drug (AED) treatment, the study of theAlthough epilepsy is one of the most common neurological disorders and genetic factors are well known to play a role in response to antiepileptic drug (AED) treatment, the study of the pharmacogenetics of epilepsy has received relatively little attention and has not resulted in clinical applications to date. Our improved understanding of the pathogenesis of epilepsy and the mechanism of action of AEDs, together with recent advances in genetics and decreasing genotyping costs, have now paved the way for a more systematic application of pharmacogenetics in the field of epilepsy. It is hoped that the resulting knowledge will lead to a more rational treatment of epilepsy, development of more efficacious AEDs, and facilitation of clinical trials of new AEDs. However, there are formidable practical, methodological and theoretical hurdles to overcome before pharmacogenomic information will have any major utility in the clinical setting. Here, we discuss the evidence for a genetic contribution to AED response, review current knowledge in epilepsy pharmacogenetics and discuss potential future avenues with their implications, both for the clinical treatment of epilepsy and new AED development.

• The potential of pharmacogenetics in the treatment of epilepsy.

  Authors: Chantal Depondt

  European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 04/2006; 10(2):57-65.

  Pharmacogenetics studies how genetic variants influence individual drug responses. Although pharmacogenetics is currently the subject of intensive research in several disease domains, it remainsPharmacogenetics studies how genetic variants influence individual drug responses. Although pharmacogenetics is currently the subject of intensive research in several disease domains, it remains relatively unexplored in the field of epilepsy. Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions and optimal doses in individual patients. Moreover, a substantial fraction of patients develop drug refractory epilepsy despite optimal treatment. Insights in the pathogenesis of epilepsy and the mechanisms of action of antiepileptic drugs (AEDs) have improved our understanding of the genetic determinants of AED response. The first reports in epilepsy pharmacogenetics are becoming available, and large-scale pharmacogenetic studies are now possible thanks to recent advances in genetics and decreasing genotyping costs. It is hoped that ultimately, findings in epilepsy pharmacogenetics will lead to a more efficacious and less harmful treatment of epilepsy, development of more effective AEDs and facilitation of clinical trials of new AEDs. However, although pharmacogenetics will undoubtedly improve our insight into the mechanisms underlying response to AEDs and perhaps into the pathogenesis of drug refractory epilepsy, clinical application of any findings is expected to be a long process, and considerable practical and theoretical hurdles need to be overcome before pharmacogenetic information will prove of any major utility in the clinical setting. This review addresses current knowledge on genetic factors contributing to AED response and discusses the potential of epilepsy pharmacogenetics in the clinical treatment of epilepsy and new AED development.

• Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?

  Authors: Gianpiero L Cavalleri, John M Lynch, Chantal Depondt, Mari-Wyn Burley, Nicholas W Wood, Sanjay M Sisodiya, David B Goldstein

  Brain : a journal of neurology. 09/2005; 128(Pt 8):1832-40.

  Temporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic riskTemporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic risk factors. Here we examine all previous claims of association of genetic polymorphisms with TLE by attempting replication in a cohort of 339 TLE patients of European origin. We also examine if these variants contribute to other types of epilepsy by examination in a larger cohort of 752 patients representing a range of different epilepsies. We fail to clearly replicate any of the previously reported associations and also fail to show a role for these variants in the development of other forms of epilepsy. Although our results cannot definitively rule out a role for these genes, they do suggest that most and perhaps all of the previous associations are false positives. As has been the experience with other diseases, these results highlight the importance of larger sample sizes and replication. In TLE, it appears that collaboration before publication is the best option to increase sample size sufficiently in the short term. These general principles are applicable to other studies undertaken for common complex diseases.

• Commentary on "A genome wide linkage disequilibrium screen in Parkinson's disease" by Foltynie et al. in J Neurol (2005) 252:597-602.

  Authors: Nicholas W Wood, Daniel G Healy, Chantal Depondt, Patrick M Abou-Sleiman

  Journal of neurology. 06/2005; 252(5):603-4.

• Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.

  Authors: Sarah K Tate, Chantal Depondt, Sanjay M Sisodiya, Gianpiero L Cavalleri, Stephanie Schorge, Nicole Soranzo, Maria Thom, Arjune Sen, Simon D Shorvon, Josemir W Sander, Nicholas W Wood, David B Goldstein

  Proceedings of the National Academy of Sciences of the United States of America. 05/2005; 102(15):5507-12.

  Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined byPhenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the alpha-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.

• Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene.

  Authors: Nicole Soranzo, Gianpiero L Cavalleri, Michael E Weale, Nicholas W Wood, Chantal Depondt, Richard Marguerie, Sanjay M Sisodiya, David B Goldstein

  Genome research. 07/2004; 14(7):1333-44.

  The difficulty of fine localizing the polymorphisms responsible for genotype-phenotype correlations is emerging as an important constraint in the implementation and interpretation of geneticThe difficulty of fine localizing the polymorphisms responsible for genotype-phenotype correlations is emerging as an important constraint in the implementation and interpretation of genetic association studies, and calls for the definition of protocols for the follow-up of associated variants. One recent example is the 3435C>T polymorphism in the multidrug transporter gene ABCB1, associated with protein expression and activity, and with several clinical conditions. Available data suggest that 3435C>T may not directly cause altered transport activity, but may be associated with one or more causal variants in the poorly characterized stretch of linkage disequilibrium (LD) surrounding it. Here we describe a strategy for the follow-up of reported associations, including a Bayesian formalization of the associated interval concept previously described by Goldstein. We focus on the region of high LD around 3435C>T to compile an exhaustive list of variants by (1) using a relatively coarse set of marker typings to assess the pattern of LD, and (2) resequencing derived and ancestral chromosomes at 3435C>T through the associated interval. We identified three intronic sites that are strongly associated with the 3435C>T polymorphism. One of them is associated with multidrug resistance in patients with epilepsy (chi2 = 3.78, P = 0.052), and sits within a stretch of significant evolutionary conservation. We argue that these variants represent additional candidates for influencing multidrug resistance due to P-glycoprotein activity, with the IVS 26+80 T>C being the best candidate among the three intronic sites. Finally, we describe a set of six haplotype tagging single-nucleotide polymorphisms that represent common ABCB1 variation surrounding 3435C>T in Europeans.

• Selection and evaluation of tagging SNPs in the neuronal-sodium-channel gene SCN1A: implications for linkage-disequilibrium gene mapping.

  Authors: Mike E Weale, Chantal Depondt, Stuart J Macdonald, Alice Smith, Poh San Lai, Simon D Shorvon, Nicholas W Wood, David B Goldstein

  American journal of human genetics. 10/2003; 73(3):551-65.

  Association studies are widely seen as the most promising approach for finding polymorphisms that influence genetically complex traits, such as common diseases and responses to their treatment.Association studies are widely seen as the most promising approach for finding polymorphisms that influence genetically complex traits, such as common diseases and responses to their treatment. Considerable interest has therefore recently focused on the development of methods that efficiently screen genomic regions or whole genomes for gene variants associated with complex phenotypes. One key element in this search is the use of linkage disequilibrium to gain maximal information from typing a selected subset of highly informative single-nucleotide polymorphism (SNP) markers, now often called "tagging SNPs" (tSNPs). Probably the most common approach to linkage-disequilibrium gene mapping involves a three-step program: (1) characterization of the haplotype structure in candidate genes or genomic regions of interest, (2) identification of tSNPs sufficient to represent the most common haplotypes, and (3) typing of tSNPs in clinical material. Early definitions of tSNPs focused on the amount of haplotype diversity that they explained. To select tSNPs that would have maximal power in a genetic association study, however, we have developed optimization criteria based on the r2 measure of association and have compared these with other criteria based on the haplotype diversity. To evaluate the full program and to assess how well the selected tags are likely to perform, we have determined the haplotype structure and have assessed tSNPs in the SCN1A gene, an important candidate gene for sporadic epilepsy. We find that as few as four tSNPs are predicted to maintain a consistently high r2 value with all other common SNPs in the gene, indicating that the tags could be used in an association study with only a modest reduction in power relative to direct assays of all common SNPs. This implies that very large case-control studies can be screened for variation in hundreds of candidate genes with manageable experimental effort, once tSNPs are identified. However, our results also show that tSNPs identified in one population may not necessarily perform well in another, indicating that the preliminary study to identify tSNPs and the later case-control study should be performed in the same population. Our results also indicate that tSNPs will not easily identify discrepant SNPs, which lie on importantly discriminating but apparently short genealogical branches. This could significantly complicate tagging approaches for phenotypes influenced by variants that have experienced positive selection.